Persistent pulmonary hypertension (PPHN) contributes significantly to neonatal mortality and morbidity. However, its pathogenesis and proper treatment remain poorly understood. The disease state is characterized by severe hypertension, abnormal pulmonary vasoreactivity, structural remodeling of the pulmonary circulation, right to left shunting across the ductus arteriosus and foramen ovale. Current therapy involves use of systemic pressors to increase systemic blood pressure, hyperventilation induced respiratory alkalosis and use of systemically administered vasodilators. This "conventional" therapy is often unsuccessful. In many cases, the therapy (in particular, the pulmonary barotrauma associated with hyperventilation) may exacerbate the pathologic process. Infants who fail conventional therapy are then placed on extracorporeal membrane oxygenation (ECMO). ECMO has been successful in improving survival in PPHN, but is labor intensive, costly, and required permanent ligation of the right carotid artery and internal jugular vein. The goals of the studies in this SCOR application are an attempt to better understand the pathogenesis of PPHN. This goal is to be achieved through basic animal research with parallel clinical studies following up promising leads from the animal research. The second goal, to be achieved through better understanding of the pathogenic process, is to devise improved specific therapy for this condition that will, hopefully, decrease the number of children in need of ECMO. The role of the clinical core is to facilitate the organization, collection of data, and analysis of data for the clinical studies proposed in this application.